A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease

PLoS One. 2013;8(2):e56695. doi: 10.1371/journal.pone.0056695. Epub 2013 Feb 19.

Abstract

Background: Klotho was originally identified in a mutant mouse strain unable to express the gene that consequently showed shortened life spans. In humans, low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults. However, it is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD).

Methods: We determined the levels of serum soluble Klotho in 114 patients with CKD using ELISA and investigated the relationship between the level of Klotho and markers of CKD-mineral and bone disorder (CKD-MBD) and various types of vascular dysfunction, including flow-mediated dilatation, a marker of endothelial dysfunction, ankle-brachial pulse wave velocity (baPWV), a marker of arterial stiffness, intima-media thickness (IMT), a marker of atherosclerosis, and the aortic calcification index (ACI), a marker of vascular calcification.

Results: The serum Klotho level significantly correlated with the 1,25-dihydroxyvitamin D level and inversely correlated with the parathyroid hormone level and the fractional excretion of phosphate. There were significant decreases in serum Klotho in patients with arterial stiffness defined as baPWV≥1400 cm/sec, atherosclerosis defined as maximum IMT≥1.1 mm and vascular calcification scores of ACI>0%. The serum Klotho level was a significant determinant of arterial stiffness, but not endothelial dysfunction, atherosclerosis or vascular calcification, in the multivariate analysis in either metabolic model, the CKD model or the CKD-MBD model. The adjusted odds ratio of serum Klotho for the baPWV was 0.60 (p = 0.0075).

Conclusions: Decreases in the serum soluble Klotho levels are independently associated with signs of vascular dysfunction such as arterial stiffness in patients with CKD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could improve arterial stiffness in CKD patients is warranted.

MeSH terms

  • Aged
  • Atherosclerosis / blood
  • Biomarkers / blood
  • Female
  • Glucuronidase / blood*
  • Humans
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Pulse Wave Analysis
  • Renal Insufficiency, Chronic / blood*
  • Renal Insufficiency, Chronic / physiopathology
  • Risk Factors
  • Vascular Calcification / blood
  • Vascular Stiffness

Substances

  • Biomarkers
  • Glucuronidase
  • klotho protein

Grant support

A portion of this study was supported by a Research Grant from the Kidney Foundation Japan (JKFB10-20 and JKFB12-44) and a 2011 Chronic Kidney Disease Award to M.K., a Research Grant from the Japan Vascular Disease Research Foundation to H.S. and a Grant-in-Aid for Progressive Renal Diseases Research, Research on Intractable Disease, from the Ministry of Health, Labor and Welfare of Japan. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.